Targeting new N-furfurylated 4-chlorophenyl-1,2,4-triazolepropionamide hybrids as potential 15-lipoxygenase inhibitors supported with in vitro and in silico studies

Abstract

Lipoxygenases (LOXs) are a group of enzymes that catalyze the oxidation of polyunsaturated fatty acids and initiate the biosynthesis of secondary metabolites that are involved to control inflammation. In search of new and more potent LOX inhibitors, a series of new 3-(5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole hybrids was prepared and screened for its LOX inhibitory potential. 4-Chlorobenzoic acid (a) was metamorphosed into N-furfuryl-5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole (4) via intermediates like benzoate (1), hydrazide (2) and semicarbazide (3). Finally, triazole (4) was fused with propionamides (6a–o) and transformed it into the aimed derivatives (7a–o). The structural interpretations of the prepared derivatives (7a–o) were accomplished via FTIR, ¹H-, ¹³C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry. The inhibitory potency of the compounds against soybean 15-LOX was determined by in vitro assay using chemiluminescence method. Compounds 7a and 7f exhibited potent LOX inhibitory profiles with IC₅₀ 21.83 ± 0.56 and 25.72 ± 0.51 µM, whereas 7d and 7e showed comparable inhibitory potential with IC₅₀ values of 34.52 ± 0.39 and 39.12 ± 0.46 µM, respectively. Compounds 7a, 7f, 7d and 7e exhibited 65.58 ± 1.4%, 54.72 ± 1.3%, 58.52 ± 1.2% and 63.56 ± 1.4% blood mononuclear cells viability, respectively. Density functional theory and molecular docking studies further strengthened the studies of the synthesized compounds and these derivatives perceived to be potential ‘lead’ compounds in drug discovery as anti-LOX.

Communicated by Ramaswamy H. Sarma

Keywords:

• 15-Lipoxygenase inhibition
• computational studies
• ADME studies
• p-chlorophenyl-N-furfuryl-1,2,4-triazole propionamides
• synthesis
• characterization

Acknowledgment

Prof. N. Riaz is thankful to Prof. Dr. Harald Gross, Institute of Pharmaceutical Biology, University of Tuebingen, Tuebingen, Germany for providing NMR and Mass analysis facility. Thanks are due to the Higher Education Commission, Pakistan, for funding the NRPU Project No. 4950 to M. Ashraf wherein W. Shahid worked as research assistant.

Disclosure statement

There is no conflict of interest amongst the authors.